The invention relates to inhibitors of enzymes that catalyze phosphoryl transfer and/or that bind ATP/GTP nucleotides, compositions comprising the inhibitors, and methods of using and compositions comprising them are useful for treating or modulating disease in which phosphoryl transferases, including kinases, may be involved, symptoms of such disease, or the effect of other physiological events mediated by phosphoryl transferases, including kinases. The invention also provides for methods of making the inhibitor compounds and methods for treating diseases in which one or more phosphoryl transferase, including kinase, activities is involved.
Phosphoryl transferases are a large family of enzymes that transfer phosphorous-containing groups from one substrate to another. Kinases are a class of enzymes that function in the catalysis of phosphoryl transfer. The protein kinases constitute the largest subfamily of structurally related phosphoryl transferases and are responsible for the control of a wide variety of signal transduction processes within the cell. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The protein kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, histidine, etc.).
The “kinase domain” appears in a number of polypeptides which serve a variety of functions. Such polypeptides include, for example, transmembrane receptors, intracellular receptor associated polypeptides, cytoplasmic located polypeptides, nuclear located polypeptides and subcellular located polypeptides. The activity of protein kinases can be regulated by a variety of mechanisms. It must be noted, however, that an individual protein kinase may be regulated by more than one mechanism. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, protein-polynucleotide interactions, ligand binding, and post-translational modification.
Protein and lipid kinases regulate many different cell processes including, but not limited to, proliferation, growth, differentiation, metabolism, cell cycle events, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to targets such as proteins or lipids. Phosphorylation events catalyzed by kinases act as molecular on/off switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. Protein and lipid kinases can function in signaling pathways to activate or inactivate, or modulate the activity of (either directly or indirectly) the targets. These targets may include, for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases and disease conditions, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis.
Initial interest in protein kinases as pharmacological targets was stimulated by the findings that many viral oncogenes encode structurally modified cellular protein kinases with constitutive enzyme activity. These findings pointed to the potential involvement of oncogene related protein kinases in human proliferative disorders. Subsequently, deregulated protein kinase activity, resulting from a variety of more subtle mechanisms, has been implicated in the pathophysiology of a number of important human disorders including, for example, cancer, CNS conditions, and immunologically related diseases. The development of selective protein kinase inhibitors that can block the disease pathologies and/or symptoms resulting from aberrant protein kinase activity has therefore generated much interest.
Protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. A partial list of such kinases includes abl, Atk, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70.
Inhibition of such kinases has become an important therapeutic target.
The ErbB receptor family belongs to the subclass I receptor tyrosine kinase superfamily and includes four distinct receptors including epidermal growth factor receptor (EGFR or ErbB1). Erb132 (HER22 or p185neu). Erb133 (HER3), and Erb134 (HER4 or rvro2).
EGFR or ErbB I has been implicated in human malignancy and, in particular, increased expression of this gene has been observed in more aggressive carcinomas of the breast, bladder, lung and stomach. Increased EGFR expression is reported to be associated with increased production of transforming growth factor-alpha (TGF-alpha), resulting in receptor activation by an autocrine stimulatory pathway. Monoclonal antibodies directed against the EGFR, or its ligands TGF-alpha and EGF. have been evaluated as therapeutic agents in the treatment of such malignancies.
While EGF and TGF-alpha do not bind ErbB2, EGF stimulates ErbBI and ErbB2 to form a heterodimer, which activates ErbB I and results in transphosphorylation of ErbB2 in the heterodimer. Dimerization and/or transphosphorylation appears to activate the ErbB2 tyrosine kinase.
While heregulin polypeptides were first identified based on their ability to activate the ErbB2 receptor it was discovered that certain ovarian cells expressing neu and neu-transfected fibroblasts did not bind or cross-link to NDF, nor did they respond to NDF to undergo tyrosine phosphorylation
Other biological role(s) of various ErbB ligands have been investigated by several groups. For example, betacellulin has been reported to exhibit growth-promoting activity in vascular smooth muscle cells and retinal pigment epithelial cells. It has been found that ARIA plays a role in myotube differentiation, namely affecting the synthesis and concentration of neuro transmitter receptors in the postsynaptic muscle cells of motor neurons. ARIA has also been demonstrated to increase the number of sodium channels in muscle. It has also been shown that GGFII is mitogenic for subconfluent quiescent human myoblasts and that differentiation of clonal human myoblasts in the continuous presence of GGFII results in greater numbers of myotubes after six days of differentiation.
The potential role(s) that the various ErbB ligands may play in pancreatic cell proliferation and differentiation has also been reported by several investigators. Islet cells (also referred to as Islets of Langerhans) in the pancreas are known to produce the hormones insulin and glucagon. Such islet cells are believed to be derived from stem cells in the fetal ductular pancreatic endothelium.
Various investigators have reported on the effects of particular EGF, heregulin and heregulin related polypeptides on islet cells.
U.S. Pat. No. 5,215,569, issued Jun. 1, 1993, describes substituted pyridines as herbicides. WO99/01136 describes substituted imidazoles as p38 inhibitors. WO00/43373 describes pyrimidinones as kinase inhibitors. Shapiro et al. (J. Amer. Chem. Soc., 79, 5064-71 (1957)) describe guanamines as potential diuretics. U.S. Pat. No. 3,136,816, issued Jun. 9, 1964, describe guanamines as potential diuretics. WO99/65909 describes pyrrolopyrimidine compounds as kinase inhibitors. WO97/19065 describes anilinopyrimidines as kinase inhibitors. U.S. Pat. No. 2,474,194, issued Jun. 21, 1949, describe guanamines as plastic additives. Swiss patent 261812 describes the preparation of triazines. British patent 1,390,235 describes trisubstituted triazines as agents for the treatment of the hormone system. U.S. Pat. No. 5,929,080 describes acrylamide derivatives for the treatment of polycystic kidney disease. Smaill et al. (J. Med. Chem., 44, 429-40 (2001)) describe acrylamides as inhibitors of the EGF receptor.
However, compounds of the current invention have not been described for the treatment of cancer or as kinase inhibitors.